At a Glance

Antithrombin deficiency is an inherited venous thrombotic disorder. A history of unexplained venous thrombosis in a patient less than 50 years of age with a family history of venous thrombosis should prompt consideration of antithrombin deficiency. First, venous thrombosis with antithrombin deficiency typically occurs in otherwise healthy individuals at approximately 30 years of age. Thrombosis may be triggered by surgery, trauma, pregnancy, or prolonged immobilization, such as car or plane rides longer than 8 hours. Venous thrombosis associated with antithrombin deficiency may occur in unusual locations, such as the portal vein, mesenteric vein, superior sagittal sinus, or arm veins and in multiple veins simultaneously. Any of these indicators of unusual venous thrombosis should prompt consideration of antithrombin deficiency.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The most useful test for evaluating possible antithrombin deficiency is an antithrombin activity assay. Antithrombin activity is preferred over antithrombin antigen assays, as activity assays detect both low levels of antithrombin production and abnormal or dysfunctional antithrombin that leads to low activity, even though antigen levels may be normal. Typically, an antithrombin activity of less than about 75% of normal suggests a possible antithrombin deficiency. If the antithrombin activity is low, it should be repeated to confirm the finding prior to establishing a diagnosis of antithrombin deficiency.

If the patient has confirmed low antithrombin activity, antithrombin antigen levels can be run to determine whether the patient has type 1 antithrombin deficiency (i.e., low levels of activity and antigen indicative of decreased production of antithrombin) or type 2 (i.e., low levels of activity with normal antigen indicative of an abnormal antithrombin molecule).

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Antithrombin levels should not be measured in patients on heparin, low molecular weight heparin therapy, or asparaginase therapy, as these medications can reduce antithrombin levels up to 30%, leading to falsely low estimates of baseline antithrombin activity. Wait at least 10 days after the medications have been stopped before measuring antithrombin activity.

Antithrombin levels may also be transiently decreased in patients with extensive venous thrombosis, portal vein thrombosis or disseminated intravascular coagulation (DIC) due to consumption of antithrombin in the clotting process. Wait until the patient has recovered from the current thrombotic episode before measuring antithrombin activity. Patients with severe hepatocellular liver disease or nephrotic syndrome may have reduced antithrombin levels due, respectively, to reduced production or loss of the protein in the urine.

Patients on warfarin or direct thrombin inhibitors, such as argatroban, bivalirudin, or dabigatran, may have falsely high antithrombin levels, so it is better to wait until the patient is off these medications and has a normal prothrombin time before measuring antithrombin activity.

Antithrombin levels are remarkably similar in all humans. The antithrombin concentration in blood does not vary to a substantial extent with time of day, race, age, sex, or menstrual cycle.

What Lab Results Are Absolutely Confirmatory?

Genetic testing for antithrombin mutations is not routinely done, as there are many different mutations that can cause antithrombin deficiency, the cost of testing is high, clinical availability is low, and definitive diagnosis is poor, unless the mutation is previously well described and known to be associated with deficiency and increased risk of venous thrombosis.

An antithrombin activity less than 60% of normal in a patient not on heparin, low molecular weight heparin, warfarin, or asparaginase without ongoing thrombosis, liver disease, or nephrotic syndrome is likely to have hereditary antithrombin deficiency.

Patients with antithrombin deficiency have approximately a five- to ten-fold increased risk of developing venous thrombosis, compared to individuals without inherited thrombophilia, and tend to develop venous thrombosis at a younger age, but most individuals with antithrombin deficiency never develop venous thrombosis. Antithrombin deficiency is associated with an increased risk of fetal loss and venous thrombosis during pregnancy. Testing for antithrombin deficiency does not, in practice, identify individuals who will definitely develop recurrent venous thrombosis, reduce the incidence of recurrent venous thrombosis, or alter antithrombotic therapy in most cases.

Additional Issues of Clinical Importance

Antithrombin deficiency is generally not associated with an increased risk of thrombosis in children prior to puberty, unless they also have other risk factors for venous thrombosis, such as cancer, infection, or intravascular catheters.

Antithrombin activity levels are sometimes measured in patients with “heparin resistance” or an unexplained weak response to standard doses of unfractionated heparin using activated partial thromboplastin time or activated clotting time tests.

Antithrombin activity or antigen levels are measured in some patients on long-term extracorporeal membrane oxygenators (ECMO), as this can consume antithrombin over time, reducing the effect of heparin used to prevent clotting in the oxygenator circuit.

There is no significant clinical association between antithrombin deficiency and arterial thrombosis.

Errors in Test Selection and Interpretation

Antithrombin activity is preferred over antithrombin antigen assays as activity assays detect both low levels of antithrombin production and abnormal or dysfunctional antithrombin that leads to low activity, even though antigen levels may be normal. The optimal antithrombin activity assay uses bovine thrombin, rather than human thrombin or factor Xa, to measure antithrombin activity.

The most common error in interpreting antithrombin activity results is the false diagnosis of hereditary antithrombin deficiency because of acquired low levels of antithrombin activity associated with heparin therapy or ongoing thrombosis. Because the prevalence of antithrombin deficiency in the population is low (pretest probability is low), false positives are likely if the result is near the lower limit of the reference range.

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